Recent studies have shown that
endotoxin (LPS) administration to Syrian hamsters markedly increased hepatic
HMG-CoA reductase activity,
protein mass, and
mRNA levels, but only produced a modest increase in hepatic
cholesterol synthesis, suggesting that LPS may also influence other key
enzymes involved in the regulation of
cholesterol metabolism. In the present study, we have examined the effect of LPS and
cytokines on the activity,
protein mass, and
mRNA level of
squalene synthase, which is the first committed
enzyme in
cholesterol biosynthesis and is located at a branch point in the
mevalonate pathway. Our results demonstrate that LPS administration produces a marked decrease in the
mRNA levels of
squalene synthase. This decrease in
squalene synthase mRNA occurred very rapidly (90 min after LPS) and required relatively small doses of LPS (1 microg/100 gm
body weight). LPS also significantly decreased
squalene synthase activity and
protein mass. Finally, LPS produced a marked decrease in
squalene synthase mRNA, activity, and
protein levels when the basal levels of
squalene synthase expression were increased 4-fold by prior treatment with
bile acid binding resin,
colestipol.
Tumor necrosis factor and
interleukin-1, which mediate many of the metabolic effects of LPS, also decreased hepatic
squalene synthase activity and
mRNA levels. Taken together, our results suggest that the discordant regulation of
HMG-CoA reductase and
squalene synthase during the host response to
infection and
inflammation may have substantial effects on the regulation of substrate flux into the non-
sterol pathways of
mevalonate metabolism.